Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
Risk factors include renal impairment, concomitant use of certain drugs, age ≥ 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full Prescribing Information.
If lactic acidosis is suspected, discontinue JENTADUETO or JENTADUETO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
JENTADUETO and JENTADUETO XR tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
JENTADUETO and JENTADUETO XR should not be used in patients with type 1 diabetes, JENTADUETO is not for the treatment of diabetic ketoacidosis.
JENTADUETO and JENTADUETO XR have not been studied in patients with a history of pancreatitis, and it is unknown if using JENTADUETO or JENTADUETO XR increases the risk of developing pancreatitis in these patients.
CONTRAINDICATIONS: Severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2); acute or chronic metabolic acidosis, including diabetic ketoacidosis; hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO or JENTADUETO XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin.
Lactic Acidosis: There have been cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Additional findings included elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate pyruvate ratio; metformin plasma levels generally >5 mcg/mL.
If lactic acidosis is suspected, immediately discontinue JENTADUETO or JENTADUETO XR and institute general supportive measures promptly in a hospital setting. Prompt hemodialysis is recommended to correct the acidosis.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue and promptly notify their healthcare provider.
Recommendations to reduce the risk include:
Pancreatitis: Acute pancreatitis, including fatal pancreatitis, has been reported in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis and if suspected, promptly discontinue and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JENTADUETO or JENTADUETO XR.
Hypoglycemia: The use in combination with insulin or insulin secretagogues may increase the risk of hypoglycemia. A lower dose of insulin or insulin secretagogue may be required.
Hypersensitivity Reactions: Discontinue JENTADUETO or JENTADUETO XR, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JENTADUETO or JENTADUETO XR.
Vitamin B12 Deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually and Vitamin B12 at 2- to 3-year intervals.
Severe and Disabling Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider linagliptin as a possible cause for severe joint pain and/or disabling arthralgia and discontinue, if appropriate.
Bullous Pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue JENTADUETO or JENTADUETO XR.
Heart Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider the risks and benefits of JENTADUETO or JENTADUETO XR in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment. Monitor patients for signs and symptoms. Advise patients of the symptoms of heart failure and to immediately report such symptoms. If heart failure develops, consider discontinuation of JENTADUETO or JENTADUETO XR.
MOST COMMON ADVERSE REACTIONS (≥5%): nasopharyngitis, diarrhea, hypoglycemia (when used in combination with sulfonylurea), nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.
Linagliptin: The efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Alternative treatments should be used.